IRAP-dependent endosomal T cell receptor signalling is essential for T cell responses

Irini Evnouchidou (), Pascal Chappert, Samira Benadda, Andres Zucchetti, Mirjana Weimershaus, Marcelle Bens, Vivien Caillens, Despoina Koumantou, Sophie Lotersztajn, Peter Endert, Jean Davoust, Pierre Guermonprez, Claire Hivroz, David A. Gross and Loredana Saveanu ()
Additional contact information
Irini Evnouchidou: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Pascal Chappert: Inovarion
Samira Benadda: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Andres Zucchetti: Paris Sciences and Lettres Research University, Institut Curie, INSERM U932
Mirjana Weimershaus: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Marcelle Bens: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Vivien Caillens: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Despoina Koumantou: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Sophie Lotersztajn: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Peter Endert: Université de Paris, Institut Necker Enfants Malades, INSERM U1151, CNRS U8253
Jean Davoust: Université de Paris, Institut Necker Enfants Malades, INSERM U1151, CNRS U8253
Pierre Guermonprez: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Claire Hivroz: Paris Sciences and Lettres Research University, Institut Curie, INSERM U932
David A. Gross: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252
Loredana Saveanu: Université de Paris, Centre de recherche sur l’inflammation, INSERM U1149, CNRS ERL8252

Nature Communications, 2020, vol. 11, issue 1, 1-16

Abstract: Abstract T cell receptor (TCR) activation is modulated by mechanisms such as TCR endocytosis, which is thought to terminate TCR signalling. Here we show that, upon internalization, TCR continues to signal from a set of specialized endosomes that are crucial for T cell functions. Mechanistically, TCR ligation leads to clathrin-mediated internalization of the TCR-CD3ζ complex, while maintaining CD3ζ signalling, in endosomal vesicles that contain the insulin responsive aminopeptidase (IRAP) and the SNARE protein Syntaxin 6. Destabilization of this compartment through IRAP deletion enhances plasma membrane expression of the TCR-CD3ζ complex, yet compromises overall CD3ζ signalling; moreover, the integrity of this compartment is also crucial for T cell activation and survival after suboptimal TCR activation, as mice engineered with a T cell-specific deletion of IRAP fail to develop efficient polyclonal anti-tumour responses. Our results thus reveal a previously unappreciated function of IRAP-dependent endosomal TCR signalling in T cell activation.

Date: 2020
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DOI: 10.1038/s41467-020-16471-7

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